Open AccessVariants in mitochondrial amidoxime reducing component 1 and hydroxysteroid 17‐beta dehydrogenase 13 reduce severity of nonalcoholic fatty liver disease in children and suppress fibrotic pathways through distinct mechanisms
Author(s) -
Hudert Christian A.,
Adams Leon A.,
Alisi Anna,
Anstee Quentin M.,
Crudele Annalisa,
Draijer Laura G.,
Furse Samuel,
Hengstler Jan G.,
Jenkins Benjamin,
Karnebeek Kylie,
Kelly Deirdre A.,
Koot Bart G.,
Koulman Albert,
Meierhofer David,
Melton Phillip E.,
Mori Trevor A.,
Snowden Stuart G.,
Mourik Indra,
Vreugdenhil Anita,
Wiegand Susanna,
Mann Jake P.
Publication year - 2022
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1955
Subject(s) - nonalcoholic fatty liver disease , medicine , odds ratio , genotype , steatosis , allele , biology , endocrinology , cd36 , fatty liver , gastroenterology , bioinformatics , disease , gene , genetics , receptor
Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 ( HSD17B13 ) and mitochondrial amidoxime reducing component 1 ( MTARC1 ) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13 , rs2642438G>A in MTARC1 , and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 ( PNPLA3 ). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation ( p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis ( p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1 . Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.